Kupffer cell-mediated lymphocyte apoptosis. A PGE₂-dependent mechanism of portal venous transfusion-induced immunosuppression?

Background. Kupffer cells, after exposure to alloantigen via the portal vein, mediate an immunosuppressive effect involving enhanced production of PGE₂. We hypothesize that up-regulation of Kupffer cell CoA-independent transacylase (CoA-IT) by portal venous transfusion (PVT) is a possible mechanism of increased PGE₂ production. Additionally, enhanced lymphocyte apoptosis, a process known to be macrophage dependent and facilitated by PGE₂, is postulated as a possible mechanism of PVT-induced, Kupffer cell- mediated immunosuppression. Methods. Lewis rat Kupffer cells were isolated after portal venous infusion with 1 ml of Wistar-Firth blood (PVT) or saline (PV sal). Kupffer cell PGE₂ production and CoA-IT activity was assessed. Lymphocyte apoptosis after exposure to PVT or PV saltreared Kupffer cells was also assessed by flow cytometry. Results. PVT-treated Kupffer cells produced significantly more PGE₂ and had increased CoA-IT activity when compared to PV sal-treated Kupffer cells. Treatment of Kupffer cells with a selective inhibitor of CoA-IT significantly decreased PVT-induced Kupffer cell PGE₂ production. Increased lymphocyte apoptosis was observed after coculture with PVT-treated Kupffer cells compared to PV sal-treated cells. Conclusions. PVT increases Kupffer cell PGE₂ production via increased CoA-IT activity and induces Kupffer cell-mediated lymphocyte apoptosis. Lymphocyte apoptosis facilitated by Kupffer cells within the hepatic sinusoid may be an important mechanism of PTV-induced immunosuppression in organ transplantation.